JP2003511450A - t-Butyl- (7-methyl-imidazo [1,2-a] pyridin-3-yl) -amine derivative - Google Patents

Abstract

  (57) [Summary] The present invention comprises a t-butyl- (7-methyl-imidazo [1,2-a] pyridin-3-yl) -amine derivative of the general formula (I), a process for its preparation and the above compound Related to pharmaceuticals. The invention further relates to the use of t-butyl- (7-methyl-imidazo [1,2-a] pyridin-3-yl) -amine derivatives for the manufacture of NO-synthase inhibitors and especially for the treatment of migraine. -Butyl- (7-methyl-imidazo [1,2-a] pyridin-3-yl) -amine derivatives for use in pharmaceutical compositions.

Description

Detailed Description of the Invention

The present invention provides a t-butyl- (7-imidazo [1,2-a] pyridin-amine derivative, a process for producing the same, a drug containing the same, a drug for inhibiting NO synthase, and particularly a drug for treating migraine. Method of Using t-Butyl- (7-imidazo [1,2-a] pyridin-amine Derivatives for the Preparation as well as t-Butyl- (7-imidazo [1,2
-A] relates to pharmaceutical formulations containing a pyridin-amine derivative.

Nitric oxide (NO) regulates many physiological processes, notably smooth muscle neurotransmission, relaxation and proliferation, platelet adhesion and aggregation, and tissue damage and inflammation. Based on multiple signal functions, NO is associated with a range of diseases (eg LJ
Ignarro, Angew. Chem. (1999), 111, 2002-2013 and F. Murad.Angew. Chem.
Int. Ed. (1999), 111, 1976-1989). In doing so, the enzymes involved in the physiological formation of NO, namely NO synthase (N
OS) plays an important role. To date, three different isoforms of NO synthase,
That is, two structural types, nNOS and eNOS, and inducible type iNOS have been identified (AJ Hobbs, A. Higgs, S. Moncada, Annu. Rev. Pharmacol. Toxicol.
. (1999), 39, 191-220; ICGreen, P.-E. Chabrier, DDT (1999), 4, 47-49;
P.-E. Chabrier et al., Cell. Mol. Life Sci. (1999), 55, 1029-1035).

Inhibition of NO synthase is associated with various diseases associated with NO (AJ Hobbs, A. Higgs, S
. Moncada, Annu. Rev. Pharmacol. Toxicol. (1999), 39, 191-220; ICGreen
, P.-E. Chabrier, DDT (1999), 4, 47-49; P.-E. Chabrier et al., Cell. Mol. L.
ife Sci. (1999), 55, 1029-1035), for example migraine (LL Thomsen.J.Olesen.
Clinical Neuroscience (1998), 5, 28-33; LHLassen et al., The Lancet (199 '
9, 349, 401-402), septic shock, neurodegenerative diseases such as multiple sclerosis, Parkinson's disease, Alheimer's disease or Hutchington's disease, inflammation, inflammatory distress, cerebral ischemia, diabetes, meningitis, arteries Disclosed are novel therapeutic clues for sclerosis. Furthermore, NOS inhibition has effects on wound healing, on tumors and on amniogenesis (Angiogenese), and causes non-specific immunity to microorganisms (AJ Hobbs et al., Annu.
Rev. Pharmacol. Toxicol. (1999), 39, 191-220).

[0004] To date, known effective substances that inhibit NO synthase are L-NMMA and L-N.
AME, ie, in addition to the homologue of L-arginine formed from NO and citrulline in vivo under the formation of NOS, in particular S-methyl-L-citrulline, aminoguanidine, S-methyl Guanidine, S-methylisourea, 7-nitroindazole and 2-mercaptoethylguanidine (AJ Hobbs et al.
Annu. Rev. Pharmacol. Toxicol. (1999), 39, 191-220).

On the contrary, the object of the present invention is to provide new and effective NOS-inhibitors.

[0006]   Surprisingly, the inventor has found that the general formula (I)

[0007]

[Chemical 13] Wherein R ¹ means H or C ₁ -C ₄ -alkanyl, where alkanyl is straight-chain or branched and unsubstituted or 1 or multiply substituted, And R ² is linear or branched and saturated or unsaturated and unsubstituted or mono- or multiply substituted C ₁ -C ₈ -alkyl radicals; saturated or unsaturated There and C ₃ -C ₈ are as or 1 or multiplexed substituted unsubstituted - cycloalkyl group; a saturated or unsaturated and unsubstituted or one or heterocyclyl group which is multiplexed substituted; Unsubstituted or mono- or multiply-substituted aryl group; unsubstituted or mono- or multiply-substituted heteroaryl group; alkyl saturated or unsaturated and Chain or branched and has and unsubstituted or 1 or and are multiplexed substituted cycloalkyl is saturated or unsaturated and unsubstituted or 1 or C ₁ -C being multiplexed substituted ₈ - alkyl -C ₃ -C ₈ - cycloalkyl; alkyl saturated or unsaturated and is or 1 or multiple substitutions is provided and unsubstituted branched or straight-chain and OriKatsu heterocyclyl C ₁ -C ₈ -alkyl-heterocyclyl which is saturated or unsaturated and is unsubstituted or mono- or multiply-substituted; alkyl is saturated or unsaturated and is linear or branched. C cage and the non location or a conversion or 1 or multiple substituted and and aryl is unsubstituted or 1 or multiple substituted ₁ -C ₈ - alkyl -Aryl; or alkyl is saturated or unsaturated and linear or branched and unsubstituted or 1 or multiply substituted and heteroaryl is unsubstituted or 1 or By multiply substituted C ₁ -C ₈ -alkyl-heteroaryl is meant. ] 3-t-Butyl-amino-substituted imidazole [1,2-a] pyridine represented by the formula, a compound in the form of its base or a pharmaceutically acceptable salt thereof is very effective NO
It was found to be an S-inhibitor.

These compounds are themselves 3-t-butyl-amino-substituted imidazole [1,2-a] pyridines [H. Bienyme of the general formula (I) in which R ¹ represents methyl and R ² represents phenyl. And K. Bouzid, Angew. Chem. (1998), 110, 2349-2352, but does not disclose that it is effective in NOS-inhibition (or any other pharmacological or therapeutic)]. Is new except. Therefore, this non-novel compound also inhibits NO-synthase and migraine, septic shock,
Multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, inflammation,
Use of it in a medicament for the treatment of inflammatory distress, cerebral ischemia, diabetes, meningeal salt, arteriosclerosis and / or wound healing, and especially its use in the manufacture of a medicament and containing it As far as the pharmaceutical composition is concerned, it is the subject of the present invention.

The term “C ₁ -C ₈ -alkyl”, in the context of the present invention, is branched or straight-chain, unsubstituted or 1 or multiply-substituted C ₁ -atoms.
8 acyclic saturated or unsaturated hydrocarbon residues, ie C ₁ -C ₈ -alkanyl,
C ₂ -C ₈ - alkenyl, and C ₂ -C ₈ - alkynyl. in this case,
Alkenyl has at least one C—C double bond and alkynyl has at least one C—C triple bond. Alkyl is methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-.
Pentyl, isopentyl, neopentyl, n- hexyl, 2-hexyl, n- octyl; ethylenyl (vinyl), ethynyl, propenyl _{(-CH 2 CH = CH 2,} -CH = CH-CH 3, -C (= CH 2) -CH _3), propynyl (-CH-
Advantageously, it is selected from the group consisting of C≡CH, —C≡C—CH ₃ ), butenyl, butynyl, pentenyl, pentynyl, hexenyl, hexynyl, octenyl and octynyl.

[0010]   "C₁~ C_FourThe term "alkanyl" means, in the context of the present invention, one carbon atom.
~ 4 saturated acyclic hydrocarbon residue of 4 provided that this residue is linear or
Are branched, unsubstituted or mono- or multiply substituted. C₁ ~ C_Four-Alkanyl is preferably methyl, ethyl, n-propyl, 2-propyl
, N-butyl, isobutyl, sec-butyl or t-butyl. Particularly advantageous C ₁ ~ C_Four-Alkanyl is methyl.

The expression “C ₃ -C ₈ -cycloalkyl” in the context of the present invention is an unsubstituted or optionally mono- or polysubstituted C ₃ -C ₈ saturated or unsaturated cyclic carbonization. Means hydrogen. Preferred C ₃ -C ₈ -cycloalkyl are selected from the group comprising cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. A particularly preferred cycloalkyl is cyclohexyl.

The term “heterocyclyl” means at least 1, sometimes 2, 3,
It means a 3-, 4-, 5-, 6- or 7-membered ring organic residue having 4 or 5 heteroatoms, provided that the heteroatoms may be the same or different from each other and the cyclic residue is saturated. Or it may be unsaturated but not aromatic and unsubstituted or mono- or multiply substituted. The heterocycle may be part of a bi- or polycyclic system. Particularly preferred heteroatoms are nitrogen, oxygen and sulfur atoms. The heterocycle residue is advantageously selected from the group comprising tetrahydrofuryl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, with the general formula (via the optional ring member of the heterocycle residue I) (or (
III)) can be attached.

The term “aryl” means in the sense of the invention aromatic hydrocarbons, among them phenyl, naphthyl and anthracenyl. Aryl residue is another saturated, (
It may also be fused with (partially) unsaturated or aromatic ring systems. Any aryl residue may be present unsubstituted or mono- or multiply substituted. However, the aryl-substituents may be the same or different from each other and may be present at any possible position of the aryl. Preferred aryls can be selected from the group containing phenyl, 1-naphthyl and 2-naphthyl. Particularly preferred aryl residues for the purposes of the present invention are phenyl, 3-hydroxyphenyl, 3-methoxyphenyl, 2,3-dihydroxyphenyl, 2,3-dimethoxyphenyl and 1-naphthyl.

The term “heteroaryl” refers to at least one, and in some cases a few,
By a 5-, 6- or 7-membered ring aromatic residue containing 4 or 5 heteroatoms, the heteroatoms may be the same or different from each other and the heterocycle may be unsubstituted or 1 or multiple It may be substituted. That is, when the heterocycle is substituted, the heteroaromatic-substituents may be the same or different from each other and are at any possible position on the heteroaryl. The heterocycle may be part of a bi- or polycyclic system. Particularly preferred heteroatoms are nitrogen, oxygen and sulfur.
Heteroaryl residues include pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, indolyl, indazolyl, purinyl, pyrimidinyl, indoridinyl, quinolinyl, isoquinolinyl, quinazolinyl, carbazolyl, phenazinyl, phenothiazinyl. It is particularly advantageous to choose from the group, in which the attachment to the compounds of the general formula (I) (or (III)) is effected via any possible ring member of the heterocycle residue. Good. Particularly advantageous heteroaryl residues for the purposes of the present invention are:
Pyridin-2-yl-, pyridin-3-yl-, furan-2-yl-, furan-
3-yl-, 5-hydroxymethylene-furan-2-yl-, 5-nitro-furan-2-yl-, 5- [1.3] -dioxolane-furan-2-yl-, 5-carboxylic acid- With furan-2-yl-, thien-2-yl (2-thiophene), thien-3-yl (3-thiophene) and 5-carboxylic acid-2-thiophene (5-carboxylic acid-thien-2-yl) is there.

[0015]   "C₁~ C₈-Alkyl-C₃~ C₈-Cycloalkyl "," C₁~ C₈-A
Rukiru-Heterocyclyl "," C₁~ C₈-Alkyl-aryl "or" C ₁ ~ C₈The term "alkyl-heteroaryl" is in the sense of the invention C₁ ~ C₈-Alkyl and cycloalkyl, heterocyclyl, aryl and phenyl
Teloaryl has the meaning defined above and is cycloalkyl, heterocyclyl.
The aryl, aryl or heteroaryl residue is of the general formula (I) (or (III))
C in the compound₁~ C₈-Attached via alkyl.

“Substituted” in the meaning of the present invention in the context of “alkyl”, “alkanyl”, “alkenyl” and “alkynyl” refers to a hydrogen radical as F, Cl, Br, I, CN,
NH _2, NH- alkyl, NH- aryl, NH- heteroaryl, NH- alkyl - aryl, NH- alkyl - heteroaryl, NH- alkyl - aryl, NH- alkyl - heteroaryl, NH- heterocyclyl, NH- Alkyl-OH, N (alkyl) ₂ , N (alkyl-aryl) ₂ , N (alkyl-heteroaryl) ₂ , N (heterocyclyl) ₂ , N (alkyl-OH) ₂ , NO,
NO _2, SH, S- alkyl, S- aryl, S- heteroaryl, S- alkyl - aryl, S- alkyl - heteroaryl, S- heterocyclyl, S- alkyl -OH, S- alkyl -SH, OH , O-alkyl, O-aryl, O-
Heteroaryl, O-alkyl-aryl, O-alkyl-heteroaryl, O
- heterocyclyl, O- alkyl -OH, CHO, C (= O ) C 1-6 - _{alkyl, C (= S) C 1-6} - alkyl, C (= O) aryl, C (= S) aryl ,
C (= O) C _1-6 -alkyl-aryl,

[0017]

[Chemical 14] (M = 1, 2 or 3), C (= S) C _1-6 -alkyl-aryl, C (═O)
Heteroaryl, C (= S) heteroaryl, C (= O) -heterocyclyl,
C (= S) - heterocyclyl, CO ₂ H, CO ₂ - alkyl, CO ₂ - alkyl - _{aryl, C (= O) NH 2} , C (= O) NH- alkyl, C (= O) NH
-Aryl, C (= O) NH-heterocyclyl, C (= O) N (alkyl) ₂ , C (= O) N (alkyl-aryl) ₂ , C (= O) N (alkyl-heteroaryl) _{2, C (= O) N} ( heterocyclyl) _2, SO- alkyl, SO ₂ -
By alkyl, SO ₂ NH ₂ , SO ₃ H, cycloalkyl, aryl, heteroaryl or heterocyclyl is meant substitution, wherein multiple residues are different from or different from the multiple substituted residue, for example double It may be substituted or triple, for example, CF ₃ or or -C to the same C- atom as in the case of -CHCF ₃
It means a residue which is substituted in triplicate at different positions as in the case of H (OH) -CH = CH- CHCl 2. Multiple substitutions may be made with the same or different substituents. Especially preferred for the purposes of the present invention, "alkyl" in this context means methyl, ethyl, CH ₂ --OH or CF ₃ .

“1 or multiply substituted” in the sense of the present invention in the context of “aryl”, “heterocyclyl”, “heteroaryl” and “alkyl-aryl” means one or more hydrogens of a ring system. atoms F, Cl, Br, I, CN, NH 2, NH- alkyl, NH- aryl, NH- heteroaryl, NH- alkyl - aryl, NH
-Alkyl-heteroaryl, NH-heterocyclyl, NH-alkyl-OH
, N (alkyl) _2, N (alkyl - aryl) _2, N (alkyl - heteroaryl) _2, N (heterocyclyl) _2, N (alkyl _{-OH) 2, NO, NO 2} , SH, S- alkyl , S-cycloalkyl, S-aryl, S-heteroaryl, S-alkyl-aryl, S-alkyl-heteroaryl, S-heterosacryl, S-alkyl-OH, S-alkyl-SH, OH, O-alkyl, O-cycloalkyl, O-aryl, O-heteroaryl, O-alkyl-aryl,
O-alkyl-heteroaryl, O-heterocyclyl, O-alkyl-OH,
CHO, C (= O) C 1-6 - _{alkyl, C (= S) C 1-6} - alkyl, C (= O
) Aryl, C (= S) aryl, C (= O) C _1-6 -alkyl-aryl,

[0019]

[Chemical 15] (M = 1, 2 or 3), C (= S) C_1-6-Alkyl-aryl, C (= O)
-Heteroaryl, C (= S) -heteroaryl, C (= O) -heterocyclyl
, C (= S) -heterocyclyl, CO₂H, CO₂-Alkyl, CO₂-A
Rukyl-aryl, C (= O) NH₂, C (= O) NH-alkyl, C (= O)
NH aryl, C (= O) NH-heterocyclyl, C (= O) N (alkyl) ₂ , C (= O) N (alkyl-aryl)₂, C (= O) N (alkyl-hetero
Aryl)₂, C (= O) N (heterocyclyl)₂, S (O) -alkyl, S
(O) -aryl, SO₂-Alkyl, SO₂-Aryl, SO₂NH₂, SO ₃ H, CF₃, = O, = S, alkyl, cycloalkyl, aryl, heteroaryl
And / or heterocyclyl
1 or multiple, for example 2-, 3- or quadruple substituted, on the atom
(However, the substituent may be optionally substituted). In this case multiple placement
The substitutions are carried out with the same or different substituents. In this case, "aryl
"-F, -CF₃, -OH and -O-CH₃Are particularly preferred substituents.
“Heteroaryl” means —OH, —O—CH₃, -CH₂OH, -NO₂, -C
O₂H, -CO₂Ethyl and-[1,3] -dioxolane are particularly preferred substituents
Is. CO for "cycloalkyl"₂H and CO₂Particularly preferred substitution is ethyl
It is a base.

A pharmaceutically acceptable salt in the context of the present invention is a pharmaceutically acceptable salt of a compound of the invention according to general formula (I), especially when used in mammals and / or humans. ) Means a physiologically compatible salt.

Hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, carbonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid Alternatively, pharmaceutically acceptable salts formed from aspartic acid and a compound of the invention according to general formula (I) are preferred. Among these salts produced, among others, hydrochloride, hydrobromide, phosphate, carbonate, bicarbonate, formate, acetate,
Suitable are oxalate, succinate, tartrate, fumarate, citric acid and glutamate. Likewise particularly preferred are solvates and especially hydrates of the compounds according to the invention, for example those obtained from aqueous solutions by crystallization.

As long as the compounds of the invention of general formula (I) have at least one asymmetric center, they are in the racemic form, in the pure enantiomers and / or diastereomers or in their enantiomers or diastereomers. These compounds may be present in the form of a mixture of mers, as they are, or as pharmaceutically acceptable salts of these compounds. The mixture may be present in any arbitrary mixing ratio of stereoisomers. The chelate compounds of the general formula (I) are preferably present as enantiomerically pure compounds.

Particularly preferred compounds of the invention have the general formula (I) in which R ¹ represents H or methyl.
3-t-butyl-amino-substituted imidazo [1,2-a] pyridine of the present invention, which is in the form of its base as well as its pharmaceutically acceptable salt.

In preferred compounds, R ² is aryl or heteroaryl, especially phenyl, 1
Especially preferred is naphthyl, furyl, thienyl or pyridinyl. In this case, or -F, -CF ₃ these residues is unsubstituted, -OH, -OC
_{H 3, -CH 2 OH, -NO} 2, -CO 2 H or - [1,3] - are 1 or double substitutions at dioxolane, except in the case of double substitution of the substituent is different or the same It may be substituted with a substituent. These compounds of the present invention may exist in the form of their bases or the form of their pharmaceutically acceptable salts.

The most advantageous compounds of the invention are the bases selected from the following group of substances of general formula (I) or in the form of their pharmaceutically acceptable salts: t-butyl- (7 -Methyl-2-pyridin-3-yl-imidazo [1,2-a]
Pyridin-3-yl) -amine, t-butyl- [2- (2,3-dimethoxy-phenyl) -5,7-dimethyl-imidazo [1,2-a] pyridin-3-yl) -amine, 3 -(3-t-Butylamino-5,7-dimethyl-imidazo [1,2-a] pyridin-2-yl) -phenol, 3- (3-t-butylamino-7-methyl-imidazo [1, 2-a] pyridine-
2-yl) -phenol, t-butyl- (2-furan-2-yl-5,7-dimethyl-imidazo [1,2-
a] Pyridin-3-yl) -amine, t-butyl- (7-methyl-2-naphthalen-1-yl-imidazo [1,2-a]
] Pyridin-3-yl) -amine, t-butyl- [5,7-dimethyl-2- (5-nitro-furan-2-yl) -imidazo [1,2-a] pyridin-3-yl)- Amine, [5- (3-t-butylamino-7-methyl-imidazo [1,2-a] pyridin-2-yl) furan-2-yl] -methanol, t-butyl- [2- (5- [1,3] Dioxolan-2-yl-furan-2-yl) -7-methyl-imidazo [1,2-a] pyridin-3-yl] -amine, 5- (3-t-butylamino-5) , 7-Dimethyl-imidazo [1,2-a] pyridin-2-yl) -furan-2-carboxylic acid, t-butyl- (2-furan-2-yl-7-methyl-imidazo [1,2- a] Pyridin-3-yl) -amine, t-butyl- (7-methyl-2-pyridyl 2-yl - imidazo [1,2-a]
Pyridin-3-yl) -amine, 5- (3-t-butylamino-7-methyl-imidazo [1,2-a] pyridin-
2-yl) -furan-2-carboxylic acid, t-butyl- (2-furan-2-yl-7-methyl-imidazo [1,2-a] pyridin-3-yl) -amine, t-butyl- (7-Methyl-2-pyridin-2-yl-imidazo [1,2-a]
Pyridin-3-yl) -amine, 5- (3-t-butylamino-7-methyl-imidazo [1,2-a] pyridin-
2-yl) -thiophene-2-carboxylic acid, t-butyl- (7-methyl-2-phenyl-imidazo [1,2-a] pyridine-
3-yl) -amine.

Another advantageous compound in the form of a salt of general formula (I) or in the form of a pharmaceutically acceptable salt is selected from the group: t-butyl- (2,5,7-trimethyl-imidazo) [1,2-a] pyridine-2
-Yl) -amine, t-butyl- (2-cyclohexyl-5,7-dimethyl-imidazo [1,2-a
] Pyridin-3-yl) -amine, t-butyl- (2-cyclohexyl-7-methyl-imidazo [1,2-a] pyridin-3-yl) -amine, t-butyl- (2,7-dimethyl -Imidazo [1,2-a] pyridin-3-yl) -amine.

[0027]   The present invention has the general formula (I)

[0028]

[Chemical 16] In the method for producing the compound represented by the general (II)

[0029]

[Chemical 17] Wherein R ¹ means H or C ₁ -C ₄ -alkanyl, where alkanyl is straight-chain or branched and unsubstituted or mono- or multiply-substituted. ] Aminopyridine represented by the general formula (III)

[0030]

[Chemical 18] [Wherein R ² is saturated or unsaturated and unsubstituted or mono- or polysubstituted C ₁ -C ₈ -alkyl group; saturated or unsaturated and unsubstituted or Mono- or multiply-substituted C ₃ -C ₈ -cycloalkyl group; saturated or unsaturated and unsubstituted or 1 or multi-substituted heterocyclyl group; unsubstituted or 1 Or a multi-substituted aryl group; unsubstituted or mono- or poly-substituted heteroaryl group; alkyl is linear or branched and unsubstituted or mono- or poly-substituted OriKatsu C ₁ -C cycloalkyl is saturated or or one or multiple substitutions unsaturated der Risoshite unsubstituted ₈ - Al kill -C ₃ -C ₈ - cycloalk Alkyl; straight-chain or branched and unsubstituted or mono- or multiply-substituted and heterocyclyl saturated or unsaturated and unsubstituted or 1- or multi-positioned C ₁ -C ₈ -alkyl-heterocyclyl, which is substituted; whether the alkyl is linear or branched and unsubstituted or is 1 or multiply substituted and the aryl is unsubstituted Or a C ₁ -C ₈ -alkyl-aryl radical which is 1 or multiply substituted; or an alkyl which is linear or branched and unsubstituted or which is 1 or multiply substituted and heteroaryl There C ₁ -C ₈ is or 1 or multiple substitutions unsubstituted - alkyl Le - means a heteroaryl, provided that R ¹ means methyl It does not mean R ² h phenyl to. ] The aldehyde represented by and structural formula (IV)

[0031]

[Chemical 19] Also relates to the above process, characterized in that it is reacted with t-butyl-isonitrile represented by

It is advantageous to carry out the process according to the invention in the presence of inorganic or organic Lewis or protic acids, in particular in the presence of perchloric acid which is used as a 20% strength aqueous solution.

It is advantageous to carry out the three-component reaction according to the invention in a one-pot process, in which case
1 mol of aminopyridine of (II) is reacted simultaneously with 1 mol of aldehyde of general (III) and isonitrile (IV).

The process of the present invention can also be carried out in a semi-automatic or fully automatic form as a parallel synthesis of a group of compounds of the present invention of general formula (I).

The method of the present invention can be carried out without a solvent. This method is advantageously carried out in an organic solvent, especially dichloromethane or acetonitrile. The reaction temperature and reaction time are in this case advantageously selected so that the reaction components are converted as completely as possible. Preferred reaction temperatures are 0 ° C. to 80 ° C., especially 10 ° C. to 35 ° C. The reaction time is generally preferably 5 minutes to 24 hours.

The general (II) aminopyridines, general (III) aldehydes and t-butylisonitrile of structural formula (V) used in the process of the present invention are commercially available (manufacturer:
Acros, Geer; Avocado, Port of Heysham; Aldrich, Deisenhofen; Fluka, Seel
ze; Lancaster, Muelheim; Maybridge, Tintagel; Merk, Darmstadt;
Sigma, Deisenhofen; TIC, Japan) or by methods well known in the art.

The compounds of the invention of general formula (I) can be isolated as the free base or as a salt. The free base of the compounds of the invention of the general formula (I) is obtained by the reaction carried out according to the process of the invention described above and the subsequent customary work-up. The free base thus obtained or produced without isolation in situ is, for example, an inorganic or organic acid, preferably hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulphonic acid, p-toluenesulphonic acid, carbonic acid, It can be converted into the corresponding salt by reaction with formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid or aspartic acid. Among the salts formed are the hydrochlorides, hydrobromides, phosphates, carbonates, bicarbonates, formates, acetates, oxalates, succinates, tartrates, fumarates, citrates and glutamic acid. Salt is suitable. The production of the particularly advantageous hydrochloride salt is also effected by adding trimethylsilyl chloride (TMSCI) to a base dissolved in a suitable organic solvent such as butan-2-one (methyl ethyl ketone).

As long as the compounds of general formula (I) are contained in the process according to the invention as racemates or as mixtures of the various enantiomers and / or diastereomers, these mixtures are the processes known from the prior art. Can be separated with. Suitable methods are, inter alia, chromatographic separation methods, in particular liquid chromatography methods at atmospheric or high pressure, in particular MPLC- and HPLC methods, and crystal fractionation methods. In this case in particular the individual enantiomers of the diastereomeric salts formed, for example by HPLC in a chiral phase or with chiral acids such as (+) tartaric acid, (−) tartaric acid or (+) 10-camphorsulfonic acid They can be separated from each other by crystallization.

[0039]   Furthermore, the general formula (I)

[0040]

[Chemical 20] Wherein R ¹ means H or C ₁ -C ₄ -alkanyl, where alkanyl is straight-chain or branched and unsubstituted or 1 or multiply substituted, And R ² is linear or branched and saturated or unsaturated and unsubstituted or mono- or multiply substituted C ₁ -C ₈ -alkyl radicals; saturated or unsaturated There and C ₃ -C ₈ are as or 1 or multiplexed substituted unsubstituted - cycloalkyl group; a saturated or unsaturated and unsubstituted or one or heterocyclyl group which is multiplexed substituted; Unsubstituted or mono- or multiply-substituted aryl group; unsubstituted or mono- or multiply-substituted heteroaryl group; alkyl saturated or unsaturated and Chain or branched and has and unsubstituted or 1 or and are multiplexed substituted cycloalkyl is saturated or unsaturated and unsubstituted or 1 or C ₁ -C being multiplexed substituted ₈ - alkyl -C ₃ -C ₈ - cycloalkyl; alkyl saturated or unsaturated and is or 1 or multiple substitutions is provided and unsubstituted branched or straight-chain and OriKatsu heterocyclyl C ₁ -C ₈ -alkyl-heterocyclyl which is saturated or unsaturated and is unsubstituted or mono- or multiply-substituted; alkyl is saturated or unsaturated and is linear or branched. C cage and the non location or a conversion or 1 or multiple substituted and and aryl is unsubstituted or 1 or multiple substituted ₁ -C ₈ - alkyl -Aryl; or alkyl is saturated or unsaturated and linear or branched and unsubstituted or 1 or multiply substituted and heteroaryl is unsubstituted or 1 or By multiply substituted C ₁ -C ₈ -alkyl-heteroaryl is meant. ] A drug containing at least one compound represented by the formula (1) in the form of its base or in the form of a pharmaceutically acceptable salt is also an object of the present invention. In this case, it is advantageous for the drug to contain a compound of the invention of the general formula (I) in the form of its hydrochloride salt. It is particularly advantageous for the agents according to the invention to contain in their basic or pharmaceutically acceptable salt form, in particular the hydrochloride salt, a compound selected from the following group: t-butyl- (7 -Methyl-2-pyridin-3-yl-imidazo [1,2-a]
Pyridin-3-yl) -amine, t-butyl- [2- (2,3-dimethoxy-phenyl) -5,7-dimethyl-imidazo [1,2-a] pyridin-3-yl) -amine, t -Butyl- (2,5,7-trimethyl-imidazo [1,2-a] pyridine-3
-Yl) -amine, 3- (3-t-butylamino-5,7-dimethyl-imidazo [1,2-a] pyridin-2-yl) -phenol, t-butyl- (2-cyclohexyl-5,5. 7-Dimethyl-imidazo [1,2-a
] Pyridin-3-yl) -amine, 3- (3-t-butylamino-7-methyl-imidazo [1,2-a] pyridin-
2-yl) -phenol, t-butyl- (2-furan-2-yl-5,7-dimethyl-imidazo [1,2-
a] Pyridin-3-yl) -amine, t-butyl- (7-methyl-2-naphthalen-1-yl-imidazo [1,2-a]
] Pyridin-3-yl) -amine, t-butyl- [5,7-dimethyl-2- (5-nitro-furan-2-yl) -imidazo [1,2-a] pyridin-3-yl)- Amine, [5- (3-t-butylamino-7-methyl-imidazo [1,2-a] pyridin-2-yl) furan-2-yl] -methanol, t-butyl- [2- (5- [1,3] Dioxolan-2-yl-furan-2-yl) -7-methyl-imidazo [1,2-a] pyridin-3-yl] -amine, 5- (3-t-butylamino-5) , 7-Dimethyl-imidazo [1,2-a] pyridin-2-yl) -furan-2-carboxylic acid, t-butyl- (2-furan-2-yl-7-methyl-imidazo [1,2- a] Pyridin-3-yl) -amine, t-butyl- (7-methyl-2-pyridyl 2-yl - imidazo [1,2-a]
Pyridin-3-yl) -amine, t-butyl- (2-cyclohexyl-7-methyl-imidazo [1,2-a] pyridin-3-yl) -amine, t-butyl- (2,7-dimethyl- Imidazo [1,2-a] pyridin-3-yl) -amine, 5- (3-t-butylamino-7-methyl-imidazo [1,2-a] pyridin-
2-yl) -thiophene-2-carboxylic acid, t-butyl- (7-methyl-2-phenyl-imidazo [1,2-a] pyridine-
3-yl) -amine.

[0041]   Another subject of the invention is the general formula (I)

[0042]

[Chemical 21] Wherein R ¹ means H or C ₁ -C ₄ -alkanyl, where alkanyl is straight-chain or branched and unsubstituted or 1 or multiply substituted, And R ² is linear or branched and saturated or unsaturated and unsubstituted or mono- or multiply substituted C ₁ -C ₈ -alkyl radicals; saturated or unsaturated There and C ₃ -C ₈ are as or 1 or multiplexed substituted unsubstituted - cycloalkyl group; a saturated or unsaturated and unsubstituted or one or heterocyclyl group which is multiplexed substituted; Unsubstituted or mono- or multiply-substituted aryl group; unsubstituted or mono- or multiply-substituted heteroaryl group; alkyl saturated or unsaturated and Chain or branched and has and unsubstituted or 1 or and are multiplexed substituted cycloalkyl is saturated or unsaturated and unsubstituted or 1 or C ₁ -C being multiplexed substituted ₈ - alkyl -C ₃ -C ₈ - cycloalkyl; alkyl saturated or unsaturated and is or 1 or multiple substitutions is provided and unsubstituted branched or straight-chain and OriKatsu heterocyclyl C ₁ -C ₈ -alkyl-heterocyclyl which is saturated or unsaturated and is unsubstituted or mono- or multiply-substituted; alkyl is saturated or unsaturated and is linear or branched. C cage and the non location or a conversion or 1 or multiple substituted and and aryl is unsubstituted or 1 or multiple substituted ₁ -C ₈ - alkyl -Aryl; or alkyl is saturated or unsaturated and linear or branched and unsubstituted or 1 or multiply substituted and heteroaryl is unsubstituted or 1 or By multiply substituted C ₁ -C ₈ -alkyl-heteroaryl is meant. A compound of the present invention including possible stereoisomers or a mixture of racemic or non-racemic stereoisomers represented by: NO in the form of a base or a pharmaceutically acceptable salt thereof, particularly in the form of a hydrochloride salt; It relates to use for producing a synthase inhibiting drug. The compounds of the present invention of general formula (I) have been surprisingly demonstrated as effective NOS inhibitors.

Particularly advantageous for this application according to the invention are compounds of general formula (I) in the form of a base or pharmaceutically acceptable salt selected from the group: t-butyl- (7 -Methyl-2-pyridin-3-yl-imidazo [1,2-a]
Pyridin-3-yl) -amine, t-butyl- [2- (2,3-dimethoxy-phenyl) -5,7-dimethyl-imidazo [1,2-a] pyridin-3-yl) -amine, t -Butyl- (2,5,7-trimethyl-imidazo [1,2-a] pyridine-3
-Yl) -amine, 3- (3-t-butylamino-5,7-dimethyl-imidazo [1,2-a] pyridin-2-yl) -phenol, t-butyl- (2-cyclohexyl-5,5. 7-Dimethyl-imidazo [1,2-a
] Pyridin-3-yl) -amine, 3- (3-t-butylamino-7-methyl-imidazo [1,2-a] pyridin-
2-yl) -phenol, t-butyl- (2-furan-2-yl-5,7-dimethyl-imidazo [1,2-
a] Pyridin-3-yl) -amine, t-butyl- (7-methyl-2-naphthalen-1-yl-imidazo [1,2-a]
] Pyridin-3-yl) -amine, t-butyl- [5,7-dimethyl-2- (5-nitro-furan-2-yl) -imidazo [1,2-a] pyridin-3-yl)- Amine, [5- (3-t-butylamino-7-methyl-imidazo [1,2-a] pyridin-2-yl) furan-2-yl] -methanol, t-butyl- [2- (5- [1,3] Dioxolan-2-yl-furan-2-yl) -7-methyl-imidazo [1,2-a] pyridin-3-yl] -amine, 5- (3-t-butylamino-5) , 7-Dimethyl-imidazo [1,2-a] pyridin-2-yl) -furan-2-carboxylic acid, t-butyl- (2-furan-2-yl-7-methyl-imidazo [1,2- a] Pyridin-3-yl) -amine, t-butyl- (7-methyl-2-pyridyl 2-yl - imidazo [1,2-a]
Pyridin-3-yl) -amine, t-butyl- (2-cyclohexyl-7-methyl-imidazo [1,2-a] pyridin-3-yl) -amine, t-butyl- (2,7-dimethyl- Imidazo [1,2-a] pyridin-3-yl) -amine, 5- (3-t-butylamino-7-methyl-imidazo [1,2-a] pyridin-
2-yl) -thiophene-2-carboxylic acid, t-butyl- (7-methyl-2-phenyl-imidazo [1,2-a] pyridine-
3-yl) -amine.

The t-butyl-amino-substituted imidazo [1,2-a] pyridines of the general formula (I) of the present invention are especially for the treatment of migraine in the base state or in the form of pharmaceutically acceptable salts. Can be used to manufacture the drug. Particularly advantageous in this case are compounds selected from the group: t-butyl- (7-methyl-2-pyridin-3-yl-imidazo [1,2-a]
Pyridin-3-yl) -amine, t-butyl- [2- (2,3-dimethoxy-phenyl) -5,7-dimethyl-imidazo [1,2-a] pyridin-3-yl) -amine, t -Butyl- (2,5,7-trimethyl-imidazo [1,2-a] pyridine-3
-Yl) -amine, 3- (3-t-butylamino-5,7-dimethyl-imidazo [1,2-a] pyridin-2-yl) -phenol, t-butyl- (2-cyclohexyl-5,5. 7-Dimethyl-imidazo [1,2-a
] Pyridin-3-yl) -amine, 3- (3-t-butylamino-7-methyl-imidazo [1,2-a] pyridin-
2-yl) -phenol, t-butyl- (2-furan-2-yl-5,7-dimethyl-imidazo [1,2-
a] Pyridin-3-yl) -amine, t-butyl- (7-methyl-2-naphthalen-1-yl-imidazo [1,2-a]
] Pyridin-3-yl) -amine, t-butyl- [5,7-dimethyl-2- (5-nitro-furan-2-yl) -imidazo [1,2-a] pyridin-3-yl)- Amine, [5- (3-t-butylamino-7-methyl-imidazo [1,2-a] pyridin-2-yl) furan-2-yl] -methanol, t-butyl- [2- (5- [1,3] Dioxolan-2-yl-furan-2-yl) -7-methyl-imidazo [1,2-a] pyridin-3-yl] -amine, 5- (3-t-butylamino-5) , 7-Dimethyl-imidazo [1,2-a] pyridin-2-yl) -furan-2-carboxylic acid, t-butyl- (2-furan-2-yl-7-methyl-imidazo [1,2- a] Pyridin-3-yl) -amine, t-butyl- (7-methyl-2-pyridyl 2-yl - imidazo [1,2-a]
Pyridin-3-yl) -amine, t-butyl- (2-cyclohexyl-7-methyl-imidazo [1,2-a] pyridin-3-yl) -amine, t-butyl- (2,7-dimethyl- Imidazo [1,2-a] pyridin-3-yl) -amine, 5- (3-t-butylamino-7-methyl-imidazo [1,2-a] pyridin-
2-yl) -thiophene-2-carboxylic acid, t-butyl- (7-methyl-2-phenyl-imidazo [1,2-a] pyridine-
3-yl) -amine.

Further, the compound of the general formula (I) of the present invention is septic shock, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, inflammation, inflammatory distress, cerebral ischemia, diabetes, meningeal salt, It is suitable for use in the manufacture of a medicament for the treatment of arteriosclerosis and / or for wound healing.

Also, a pharmaceutical composition containing a base or a pharmaceutically acceptable salt of at least one compound of the above-mentioned general formula (I) and a pharmaceutical composition containing one or more pharmaceutical auxiliaries. It is the subject of the present invention.

The medicaments and pharmaceutical compositions according to the invention may be in the form of liquid, semisolid or solid medicaments and for example injectable solutions, drops, solutions, syrups, sprays, suspensions, granules, tablets,
Can be present and administered in the form of pellets, bandages, capsules, ointments, suppositories, ointments, creams, lotions, gels, emulsions or aerosols,
In addition to at least one compound of the invention of general formula (I), pharmaceutical auxiliaries depending on the form of the galenical drug, such as carrier substances, fillers, solvents, diluents, surface-active substances, colorants, preservatives, Contains disintegrants, lubricants, lubricants, perfumes and / or binders.
These auxiliaries are, for example, water, ethanol, 2-propanol, glycerin, ethylene glycol, propylene glycol, polyethylene glycol, polypropylene glycol, glucose, fructose, lactose, saccharose, dextrose, molasses, starch, modified starch, gelatin, sorbitol, inositol. , Mannitol, microcellulose, methylcellulose, carboxymethylcellulose, cellulose acetate, shellac, cetyl alcohol, polyvinylpyrrolidone, paraffins, waxes, pharmaceutically acceptable natural and synthetic gums,
Gum arabic, alginate, dextran, saturated and unsaturated fatty acids, stearic acid, magnesium stearate, zinc stearate, glyceryl stearate, sodium lauryl sulfate, edible oil, sesame oil, coconut oil, peanut oil, soybean oil, lecithin, lactic acid Sodium, polyoxyethylene-and-propylene fatty acid ester, sorbitan fatty acid ester, sorbic acid, benzoic acid, citric acid, ascorbic acid, tannic acid, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, magnesium oxide, zinc oxide, dioxide Silicon, titanium oxide, titanium dioxide, magnesium sulfate, zinc sulfate, calcium sulfate, caustic potash, calcium phosphate, dicalcium phosphate, potassium bromide, potassium iodide, talc, kaolin,
There are pectin, Crospovidon, agar and bentonite.

The selection of the auxiliaries and the amounts thereof used are such that the agents are oral, subcutaneous, parenteral, intravenous, intraperitoneal, intradermal, muscular, intranasal, buccal, rectal or topical, for example skin, mucous membranes and eyes. It depends on whether it should be administered by injecting into. Preparations in the form of tablets, dragees, capsules, granules, drops, solutions and syrups are suitable for oral administration, solutions, suspensions for parenteral, topical and inhalation administration.
Easily reconstitutable dry formulations as well as spray solutions are suitable. Formula (I) in solution, in a depot or in a plaster, optionally with the addition of agents that promote skin penetration.
The compounds of the invention are suitable for suitable transdermal administration. Preparations which can be used orally or dermally can release the compounds of the invention of the general formula (I) on a delayed basis.

The preparation of the medicaments and pharmaceutical compositions according to the invention can be carried out, for example, by the method “Remington's Pharmaceutic
al Science ", Hrsg. ARGennaro, 17th Edition, Mark Publishing Company, Easton, Pa. (1985), especially in the prior art of drug preparation, as described in Volume 8, Chapters 76-93. By means, devices and methods.

In order to produce a solid pre-prepared composition containing the compound of the invention or a pharmaceutically acceptable salt thereof in a homogeneous distribution, a pharmaceutically active substance, ie a compound of general formula (I) or A pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier such as a commercially available tablet content such as corn starch, lactose, saccharose, sorbitol, talc, magnesium stearate, dicalcium phosphate or gum, and a pharmaceutical diluent, It may, for example, be mixed with water to give a solid preparation such as a tablet. By homogeneous distribution is meant that the active substance is evenly distributed throughout the pre-prepared composition, which can readily be subdivided into unit dose forms of the same potency, for example tablets, pills or capsules. The solid preformulated composition is then subdivided into unit dose forms. The tablets or pills of the agents of the invention or compositions of the invention may be coated or otherwise compounded to provide a delayed release dosage form. Suitable coating agents include polymeric acids and mixtures of polymeric acids with substances such as shellac, cetyl alcohol and / or cellulose acetate.

The effective amount to be administered to a patient will vary and will depend on the weight, age and medical history of the patient and the type of administration, symptoms and severity of the disease. Usually, 0.1 to 5000 mg, in particular 1 to 50, of at least one compound of the invention of the general formula I per kg of body weight
The dose is 0 mg, preferably 2-250 mg.

The following shows the assay used for the determination of NOS inhibition by the compounds of the present invention represented by general formula I: NOS Assay Common Method This assay is based on the percentage inhibition of NO synthase by the active substance. Can be measured by the degree of NOS activity. In this case, NO synthase is mixed with radiolabeled arginine and the active substance under suitable conditions.
After stopping the NO formation reaction at a predetermined time point, unreacted arginine is measured directly or indirectly. Comparison of this amount with the amount of arginine remaining from the mixture of NOS and arginine under the same and without addition of active substance reveals the% inhibition of NO synthase by the active substance tested. . This assay can be performed as follows: (a) Incubating NO synthase with labeled arginine as substrate in a reaction vessel. (B) The labeled arginine is separated from the labeled citrulline, which optionally occurs as a product of an enzymatic reaction, at the time when the citrulline concentration increases. (C) The amount of separated arginine is measured.

[0053]   This separation is done via a filter plate-membrane.

This NOS-assay was performed on a Microtiter plate (MTP) with "High Thro
Suitable for ughput screening "(HTS).

HTS-NOS-Assay: General Procedure In this HTS-NOS-assay, radioactive arginine is used as the substrate.
Assay volumes ranging from 25 μL to 250 μL in microtiter plates (MT
It can be selected according to the type of P). Cofactors and coenzymes are added according to the enzyme source used. Incubation of the charge (assay-MTP) in this microtiter plate according to step (a) is carried out at room temperature and then reaches 5-60 minutes depending on the enzyme activity (units) used. The plate is placed in the cell harvester until the end of the incubation (step (a)). This collector comprises an MTP with a cation exchanger membrane as filter bed (filter MT
P). All charges of assay MTP are transferred to this filter MTP and suction filtered through a cation exchanger-filter-plate, a paper filter loaded with phosphate groups. The filter MTP is then washed with buffer or water. This pretreatment binds the remaining substrate arginine to the cation exchanger, while the radioactive citrulline formed by the enzyme is quantitatively washed. After drying the filter MTP and adding scintillation fluid, bound arginine is counted in a scintillation counter. The uninhibited NOS reaction glows again with little radioactivity. An inhibited enzymatic reaction means not converting radioactive arginine. That is, high radioactivity is found on the filter.

[0056] Materials arginine used, L- [2,3,4 ³ -H] - monohydrochloride:. Best.-No NET-1123 , NE
Company N anhydrous CaCl ₂ : Best.-No.2388.1000: Merck Company 1,4-dithiothreitol (DTT). . Best.-No.708984: Roche Na ₂ EDTA-dihydrate: Best.-No.03680: FLUKA Co. HEPES, Best.-No H-3375 : Sigma NADPH, tetrasodium salt; Best.-No .1585363: Roche TRIS; BEST.-No.93349: FLUKA Enzyme-preparation buffer: Tris-HCl 50 mM with EDTA 1 mM: buffer Adjust pH value to 7.4 at 4 ° C.

Incubation buffer (medium): HEPES 50 mM with EDTA 1 mM, CaCl ₂ 1.25 mM and dithiothreitol 1 mM.

[0058]                     The pH value of the buffer is adjusted to 7.4 at 25 ° C.

Wash Medium: H ₂ O Enzyme Preparation Rat brain is used as the starting tissue. Anesthetize and kill the animal, collect brain tissue, ie, cerebellum, add 1 mL of enzyme preparation buffer (4 ° C.) per rat cerebellum, and disintegrate at 6000 U / min for 1 minute using a Polytron homogenizer. Let Then, it is centrifuged at 20000 g for 15 minutes at 4 ° C., and then the supernatant is decanted and divided into several portions and frozen at −80 ° C. (precipitation removal).

Incubation Charge <96 μ-well MTP with a “Well” volume of 250 μL, the order of pipette addition is as follows: See Table 1: Table 1: Substances Molarity in the charge μL Protein in incubation ^* Incubation buffer-100 − Test substance Not quantified; Not quantified; preferably 10 ⁻⁵ M, preferably 20 μL − NADPH 0.5 mM 20 − Enzyme not quantified; Not quantified; (see Example 3) − Maximum usable maximum volume of enzyme solution = protein mass = 50 μL 100 μg [ ³ H] Substrate indeterminate; indeterminate; preferably 50 nM, preferably 10 μL- final volume: 250 μL maximum ^* OHLowry et al. Chem. 193, 265 (1951).

After completion of the pipetting operation, the lid is placed on this MTP (assay-MTP). 5 to 60 minutes depending on the amount and activity of the enzyme used, 25 ° C (room temperature (RT))
A) Incubate with.

The assay-the content of MTP-96-using a 96-well cell harvester
Transfer to the well cation exchanger MTP (filter MTP) and filter by suction.
It is then washed once (from the tank) with ₂₀₀ ml of H ₂ O.

The plate is then dried for 1 hour at 60 ° C. in a drying cabinet. Then filter M
Seal the bottom of the TP exactly from below using a "back seal". Then wel
Pipette 35 μL of scintillator per l. Further, the upper surface of the plate is sealed with a "top seal". After leaving for 1 hour, the plate is β-
Weigh on the counter.

In the HTS operation, the incubation medium, NADPH solution and enzyme solution are combined prior to the pipetting operation, which eliminates the need for three separate time-consuming pipetting operations.

[0065]   The results of the exemplified compounds in the NOS assay are shown in Table 3.

Citrulline-Assay This assay is described, for example, in DS Bredt and SHSnyder (Proc. Natl. Acad. Sci.
Perform as described in the United States (1990), 87, 682-685). Table 4 shows the results of the exemplified compounds in the citrulline-assay.

The present invention will be described in more detail by the following examples, but the present invention is not limited to these examples.

[0068]

【Example】

Examples: The compounds of the invention were prepared according to the following general synthetic recipe (AAV).

General Synthetic Formulation 1 (AAV1) A threaded glass round bottom tube (16 mm diameter, 125 mm length) is equipped with a stirrer and sealed with a septum screw cap. The small tube is placed on a reactor table thermostatted at 15 ° C. Pipette the following reagents before and after. 1) 1 mL of 0.1 molar aminopyridine-II-solution + 20% strength HClO _{4 in} dichloromethane 2) 0.5 mL of 0.3 molar solution of aldehyde III in dichloromethane 3) t-butyl in dichloromethane -0.575 mL of 0. 2 molar solution The reaction mixture is stirred at 15 ° C. for 12 hours. Then the reaction solution is filtered. In this case, wash the tube twice with 1 mL each of dichloromethane and 200 μL of water.

The reaction mixture is mixed with 3 mL of 10% strength NaCl solution and 1.5 mL of dichloromethane and mixed well. Separate the organic phase and re-add 1.5 mL of the aqueous phase
Extract with dichloromethane. The combined organic phases are dried with 2.4 g (granulated) MgSO ₄ . Remove the solvent in a vacuum centrifuge.

The chemicals and solvents used are commercially available. Each substance is evaluated and analyzed by ESI-MS and / or NMR.

Examples 1-17 made according to AAV1 were automatically tested in the HTS-NOS-assessment analysis. The results are summarized in Table 3.

[0073]

[Table 1] As a comparative example, 7-nitroindazole was treated with NOS at an inhibition rate of 50% (10 μm).
-Test with evaluation analysis.

General Synthetic Formulation 2 (AAV2) (equivalent means material equivalent to t-butyl-isonitrile IV used) In a reaction vessel, first 1.15 equivalents of aminopyridine II (isonitrile IV used) were used. Suspend or dissolve in dichloromethane (2 mL per mmol).
This is followed by 1.5 equivalents of aldehyde III, 1 equivalent of t-butylisonitrile and finally (20% by weight: isonitrile IV used, 0 per mmol of isonitrile IV).
． Aqueous perchloric acid solution (098 mL) is added and the mixture is stirred for 12 hours at room temperature.

Saturated sodium chloride solution for working up (isonitrile VI used 1 m
about 5 mL per mol) and dichloromethane (isonitrile VI 1 used)
(about 4 mL / mmol), the phases are separated and the organic phase is diluted with dichloromethane (
Extract twice with 1 mmol of isonitrile VI used (about 2 mL).
Buffer solution (isonitrile VI used 1 mm before and after combining the combined organic phases)
about 2 mL per ol) and saturated sodium chloride solution (isonitrile used
(About 2 mL per mmol of VI), dried over sodium sulphate, filtered and concentrated under reduced pressure on a rotary evaporator and freed from solvent residues on a hydraulic vacuum pump.

The crude product obtained is directly led to the hydrochloride precipitation stage (about 10 / g of base).
Dissolve the crude base in mL of 2-butanone, add 0.5 molar equivalents of water, then 1
． Add 1 molar equivalent of chlorotrimethylsilane (TMSCl) and stir overnight) or heat with reflux (about 10 mL of nitrile per mmol of nitrile used) under reflux. If the crude product does not completely dissolve, decant it in the hot state. After cooling the hexane solution, the solid obtained is filtered off and dried under vacuum on a hydraulic vacuum pump. The filtrate obtained is concentrated on a rotary evaporator and the residue is dried again on a hydraulic vacuum pump. In this way, various fractions are obtained.

0: not treated with hexane 2: solid precipitated from hexane solution on cooling 4: residue of hexane solution concentrated to dryness Thin layer chromatography and fractionation from fractions obtained in each / Or NMR
-Identify each product fraction by a spectroscopy test. Finally, the hydrochloride salt is precipitated from some of the product fractions with TMSCI by the method described above.

The obtained Example compounds 18 to 20 were treated with citrulline (Citru) for NOS-inhibition.
llin) Perform evaluation analysis. The results are summarized in Table 4.

[0079]

[Table 2] As a comparative example, citrulline evaluation analysis, 5. of NOS-inhibitors known from the prior art.
7-Nitroindazole having an IC ₅₀ value of 23 μM is tested.

Pharmaceutical Preparation of the Agents of the Invention t-Butyl- (2-furan-2-yl-5,7-dimethyl-imidazo [1,2
1 g of the hydrochloride salt of -a] pyridin-3-yl) -amine is dissolved in 1 L of water for injection at room temperature and then adjusted to isotonic conditions by the addition of sodium chloride.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 9/10 101 A61P 9/10 101 17/02 17/02 25/00 25/00 25/14 25 / 14 25/16 25/16 25/28 25/28 29/00 29/00 31/04 31/04 43/00 111 43/00 111 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ) , MD, RU, TJ, TM), AE, AL, AM, AT , AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CR, CU, CZ, DE, DK, DM, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW , MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW (72) Inventor Hennis Hagen-Heinrich, Federal Republic of Germany, Zimmerat, Eichelschaid, 56 (72) Inventor Schneider Johannes, Federal Republic of Germany, Stolberg, Laurentstraße, 40 (72) Inventor Gellarha Matthias Germany, Braftthal, Puffergasse, 1F term (reference) 4C065 AA03 BB06 CC01 DD02 EE02 HH03 JJ01 LL07 PP04 PP06 PP07 PP12 QQ02 QQ04 QQ05 4C086 AA01 AA02 AA03 AA04 CB05 MA01 ZA35B16 ZA16 MA15 NA15 ZA15ZA15 ZA16B15ZA15 ZA15B15ZA15 ZA16B15ZA15 ZA16B15ZA16ZA15ZA16ZA15 ZC20 ZC35

Claims (19)

[Claims] 1. A compound represented by the general formula (I): Wherein R ¹ means H or C ₁ -C ₄ -alkanyl, where alkanyl is straight-chain or branched and unsubstituted or 1 or multiply substituted, And R ² is linear or branched and saturated or unsaturated and unsubstituted or mono- or multiply substituted C ₁ -C ₈ -alkyl radicals; saturated or unsaturated There and C ₃ -C ₈ are as or 1 or multiplexed substituted unsubstituted - cycloalkyl group; a saturated or unsaturated and unsubstituted or one or heterocyclyl group which is multiplexed substituted; Unsubstituted or mono- or multiply-substituted aryl group; unsubstituted or mono- or multiply-substituted heteroaryl group; alkyl saturated or unsaturated and Chain or branched and has and unsubstituted or 1 or and are multiplexed substituted cycloalkyl is saturated or unsaturated and unsubstituted or 1 or C ₁ -C being multiplexed substituted ₈ - alkyl -C ₃ -C ₈ - cycloalkyl; alkyl saturated or unsaturated and is or 1 or multiple substitutions is provided and unsubstituted branched or straight-chain and OriKatsu heterocyclyl C ₁ -C ₈ -alkyl-heterocyclyl which is saturated or unsaturated and is unsubstituted or mono- or multiply-substituted; alkyl is saturated or unsaturated and is linear or branched. C cage and the non location or a conversion or 1 or multiple substituted and and aryl is unsubstituted or 1 or multiple substituted ₁ -C ₈ - alkyl -Aryl; or alkyl is saturated or unsaturated and linear or branched and unsubstituted or 1 or multiply substituted and heteroaryl is unsubstituted or 1 or By multiply substituted C ₁ -C ₈ -alkyl-heteroaryl is meant. ] The compound represented by the following, a compound in the form of its base or a pharmaceutically acceptable salt thereof,
However, compounds of general formula (I) in which R ¹ is methyl and R ² is phenyl are excluded. 2. A compound according to claim 1, wherein R ¹ represents H or methyl, a compound in the form of its base or a pharmaceutically acceptable salt thereof. 3. The compound according to claim 1 or 2, wherein R ² represents aryl or heteroaryl, the compound in the form of its base or a pharmaceutically acceptable salt thereof. 4. A compound according to claim 3, wherein R ² is 1-naphthyl, phenyl, furyl, thienyl or pyridinyl and is unsubstituted or mono- or multiply substituted, its base or pharmaceutically. An acceptable compound in its salt form. 5. 1-naphthyl, phenyl, furyl, thienyl or or -F pyridinyl is _{unsubstituted, -CF 3, -OH, -OCH 3} , -CH 2 OH
, -NO _2, -CO ₂ H and / or - [1,3] - The compound of claim 4 which is 1- or double substitutions at dioxolane, of the base or a pharmaceutically acceptable salt thereof State compound. 6. t-Butyl- (7-methyl-2-pyridin-3-yl-imidazo [1,2-a] pyridin-3-yl) -amine, t-butyl- [2- (2,3 -Dimethoxy-phenyl) -5,7-dimethyl-imidazo [1,2-a] pyridin-3-yl) -amine, t-butyl- (2,5,7-trimethyl-imidazo [1,2-a]] Pyridine-3
-Yl) -amine, 3- (3-t-butylamino-5,7-dimethyl-imidazo [1,2-a] pyridin-2-yl) -phenol, t-butyl- (2-cyclohexyl-5,5. 7-Dimethyl-imidazo [1,2-a
] Pyridin-3-yl) -amine, 3- (3-t-butylamino-7-methyl-imidazo [1,2-a] pyridin-
2-yl) -phenol, t-butyl- (2-furan-2-yl-5,7-dimethyl-imidazo [1,2-
a] Pyridin-3-yl) -amine, t-butyl- (7-methyl-2-naphthalen-1-yl-imidazo [1,2-a]
] Pyridin-3-yl) -amine, t-butyl- [5,7-dimethyl-2- (5-nitro-furan-2-yl) -imidazo [1,2-a] pyridin-3-yl)- Amine, [5- (3-t-butylamino-7-methyl-imidazo [1,2-a] pyridin-2-yl) furan-2-yl] -methanol, t-butyl- [2- (5- [1,3] Dioxolan-2-yl-furan-2-yl) -7-methyl-imidazo [1,2-a] pyridin-3-yl] -amine, 5- (3-t-butylamino-5) , 7-Dimethyl-imidazo [1,2-a] pyridin-2-yl) -furan-2-carboxylic acid, t-butyl- (2-furan-2-yl-7-methyl-imidazo [1,2- a] Pyridin-3-yl) -amine, t-butyl- (7-methyl-2-pyridyl 2-yl - imidazo [1,2-a]
Pyridin-3-yl) -amine, t-butyl- (2-cyclohexyl-7-methyl-imidazo [1,2-a] pyridin-3-yl) -amine, t-butyl- (2,7-dimethyl- Imidazo [1,2-a] pyridin-3-yl) -amine, 5- (3-t-butylamino-7-methyl-imidazo [1,2-a] pyridin-
2-yl) -thiophene-2-carboxylic acid, t-butyl- (7-methyl-2-phenyl-imidazo [1,2-a] pyridine-
A compound according to any one of claims 1 to 5, a compound in the form of its base or a pharmaceutically acceptable salt thereof, especially the hydrochloride salt, selected from the group consisting of 3-yl) -amine. 7. A compound represented by the general formula (I) according to any one of claims 1 to 6 In the method for producing the compound represented by the general formula (II) Wherein R ¹ means H or C ₁ -C ₄ -alkanyl, where alkanyl is straight-chain or branched and unsubstituted or mono- or multiply-substituted. ] Aminopyridine represented by the general formula (III) Wherein R ² is linear or branched and saturated or unsaturated and unsubstituted or mono- or multiply-substituted C ₁ -C ₈ -alkyl group; saturated or unsaturated the C ₃ -C ₈ that has as or 1 or multiplexed substituted unsubstituted - cycloalkyl group; a saturated or unsaturated and unsubstituted der Luke or one or heterocyclyl group which is multiplexed substituted; An unsubstituted or mono- or multiply-substituted aryl group; an unsubstituted or mono- or multiply-substituted heteroaryl group; an alkyl which is linear or branched and saturated or unsaturated And and is unsubstituted or mono- or polysubstituted and cycloalkyl is saturated or unsaturated and unsubstituted or 1 or C ₁ -C ₈ is - alkyl -C ₃ -C ₈ - cycloalkyl, alkyl is provided and saturated or unsaturated and branched or straight-chain and or one or multiple substitutions unsubstituted C ₁ -C ₈ -alkyl-heterocyclyl, which is heterocyclic and is saturated or unsaturated and is unsubstituted or mono- or multiply substituted; alkyl is linear or branched And saturated or unsaturated and unsubstituted or mono- or polysubstituted and aryl unsubstituted or mono- or polysubstituted C ₁ -C ₈ -alkyl-aryl A group; or alkyl is linear or branched and saturated or unsaturated and unsubstituted or mono- or multiply substituted and C ₁ -C ₈ Teroari Lumpur is or 1 or multiple substitutions unsubstituted - alkyl Le - means a heteroaryl, provided that R ² when R ¹ means methyl does not mean phenyl. ] The aldehyde represented by and structural formula (IV) The method described above, which comprises reacting with t-butylisonitrile represented by: 8. A process according to claim 7, which is carried out in the presence of an acid, in particular perchloric acid. 9. The method according to claim 7, wherein the reaction of aminopyridine (II) with aldehyde (III) and t-butylisonitrile (IV) is carried out by a one-pot method. 10. A process according to claim 7, wherein the formed base of general formula (I) is converted to its hydrochloride salt by addition of trimethylchlorosilane. 11. A compound represented by the general formula (I): Wherein R ¹ means H or C ₁ -C ₄ -alkanyl, where alkanyl is straight-chain or branched and unsubstituted or 1 or multiply substituted, And R ² is linear or branched and saturated or unsaturated and unsubstituted or mono- or multiply substituted C ₁ -C ₈ -alkyl radicals; saturated or unsaturated There and C ₃ -C ₈ are as or 1 or multiplexed substituted unsubstituted - cycloalkyl group; a saturated or unsaturated and unsubstituted or one or heterocyclyl group which is multiplexed substituted; Unsubstituted or mono- or multiply-substituted aryl group; unsubstituted or mono- or multiply-substituted heteroaryl group; alkyl saturated or unsaturated and Chain or branched and has and unsubstituted or 1 or and are multiplexed substituted cycloalkyl is saturated or unsaturated and unsubstituted or 1 or C ₁ -C being multiplexed substituted ₈ - alkyl -C ₃ -C ₈ - cycloalkyl; alkyl saturated or unsaturated and is or 1 or multiple substitutions is provided and unsubstituted branched or straight-chain and OriKatsu heterocyclyl C ₁ -C ₈ -alkyl-heterocyclyl which is saturated or unsaturated and is unsubstituted or mono- or multiply-substituted; alkyl is saturated or unsaturated and is linear or branched. C cage and the non location or a conversion or 1 or multiple substituted and and aryl is unsubstituted or 1 or multiple substituted ₁ -C ₈ - alkyl -Aryl; or alkyl is saturated or unsaturated and linear or branched and unsubstituted or 1 or multiply substituted and heteroaryl is unsubstituted or 1 or By multiply substituted C ₁ -C ₈ -alkyl-heteroaryl is meant. ] The chemical | medical agent containing at least 1 sort (s) of the compound represented by these, its base, or the compound of the state of its pharmaceutically acceptable salt. 12. A compound represented by the general formula (I): Wherein R ¹ means H or C ₁ -C ₄ -alkanyl, where alkanyl is straight-chain or branched and unsubstituted or 1 or multiply substituted, And R ² is linear or branched and saturated or unsaturated and unsubstituted or mono- or multiply substituted C ₁ -C ₈ -alkyl radicals; saturated or unsaturated There and C ₃ -C ₈ are as or 1 or multiplexed substituted unsubstituted - cycloalkyl group; a saturated or unsaturated and unsubstituted or one or heterocyclyl group which is multiplexed substituted; Unsubstituted or mono- or multiply-substituted aryl group; unsubstituted or mono- or multiply-substituted heteroaryl group; alkyl saturated or unsaturated and Chain or branched and has and unsubstituted or 1 or and are multiplexed substituted cycloalkyl is saturated or unsaturated and unsubstituted or 1 or C ₁ -C being multiplexed substituted ₈ - alkyl -C ₃ -C ₈ - cycloalkyl; alkyl saturated or unsaturated and is or 1 or multiple substitutions is provided and unsubstituted branched or straight-chain and OriKatsu heterocyclyl C ₁ -C ₈ -alkyl-heterocyclyl which is saturated or unsaturated and is unsubstituted or mono- or multiply-substituted; alkyl is saturated or unsaturated and is linear or branched. C cage and the non location or a conversion or 1 or multiple substituted and and aryl is unsubstituted or 1 or multiple substituted ₁ -C ₈ - alkyl -Aryl; or alkyl is saturated or unsaturated and linear or branched and unsubstituted or 1 or multiply substituted and heteroaryl is unsubstituted or 1 or By multiply substituted C ₁ -C ₈ -alkyl-heteroaryl is meant. ] The method of using the compound represented by these, its base, or the compound in the form of its pharmaceutically acceptable salt, for manufacturing the chemical | medical agent for NO-synthase inhibition. 13. A compound of the general formula (I) is prepared from t-butyl- (7-methyl-2-
Pyridin-3-yl-imidazo [1,2-a] pyridin-3-yl) -amine,
t-Butyl- [2- (2,3-dimethoxy-phenyl) -5,7-dimethyl-imidazo [1,2-a] pyridin-3-yl) -amine, t-butyl- (2,5,7 -Trimethyl-imidazo [1,2-a] pyridine-3
3-yl) -amine, 3- (3-t-butylamino-5,7-dimethyl-imidazo [1,2-a] pyridin-2-yl) -phenol, t-butyl- (2-cyclohexyl-5) , 7-Dimethyl-imidazo [1,2-a
] Pyridin-3-yl) -amine, 3- (3-t-butylamino-7-methyl-imidazo [1,2-a] pyridin-
2-yl) -phenol, t-butyl- (2-furan-2-yl-5,7-dimethyl-imidazo [1,2-
a] Pyridin-3-yl) -amine, t-butyl- (7-methyl-2-naphthalen-1-yl-imidazo [1,2-a]
] Pyridin-3-yl) -amine, t-butyl- [5,7-dimethyl-2- (5-nitro-furan-2-yl) -imidazo [1,2-a] pyridin-3-yl)- Amine, [5- (3-t-butylamino-7-methyl-imidazo [1,2-a] pyridin-2-yl) furan-2-yl] -methanol, t-butyl- [2- (5- [1,3] Dioxolan-2-yl-furan-2-yl) -7-methyl-imidazo [1,2-a] pyridin-3-yl] -amine, 5- (3-t-butylamino-5) , 7-Dimethyl-imidazo [1,2-a] pyridin-2-yl) -furan-2-carboxylic acid, t-butyl- (2-furan-2-yl-7-methyl-imidazo [1,2- a] Pyridin-3-yl) -amine, t-butyl- (7-methyl-2-pyridyl 2-yl - imidazo [1,2-a]
Pyridin-3-yl) -amine, t-butyl- (2-cyclohexyl-7-methyl-imidazo [1,2-a] pyridin-3-yl) -amine, t-butyl- (2,7-dimethyl- Imidazo [1,2-a] pyridin-3-yl) -amine, 5- (3-t-butylamino-7-methyl-imidazo [1,2-a] pyridin-
2-yl) -thiophene-2-carboxylic acid, t-butyl- (7-methyl-2-phenyl-imidazo [1,2-a] pyridine-
13. The method of claim 12 selected from the group consisting of 3-yl) -amine. 14. A compound represented by the general formula (I): Wherein R ¹ means H or C ₁ -C ₄ -alkanyl, where alkanyl is straight-chain or branched and unsubstituted or 1 or multiply substituted, And R ² is linear or branched and saturated or unsaturated and unsubstituted or mono- or multiply substituted C ₁ -C ₈ -alkyl radicals; saturated or unsaturated There and C ₃ -C ₈ are as or 1 or multiplexed substituted unsubstituted - cycloalkyl group; a saturated or unsaturated and unsubstituted or one or heterocyclyl group which is multiplexed substituted; Unsubstituted or mono- or multiply-substituted aryl group; unsubstituted or mono- or multiply-substituted heteroaryl group; alkyl saturated or unsaturated and Chain or branched and has and unsubstituted or 1 or and are multiplexed substituted cycloalkyl is saturated or unsaturated and unsubstituted or 1 or C ₁ -C being multiplexed substituted ₈ - alkyl -C ₃ -C ₈ - cycloalkyl; alkyl saturated or unsaturated and is or 1 or multiple substitutions is provided and unsubstituted branched or straight-chain and OriKatsu heterocyclyl C ₁ -C ₈ -alkyl-heterocyclyl which is saturated or unsaturated and is unsubstituted or mono- or multiply-substituted; alkyl is saturated or unsaturated and is linear or branched. C cage and the non location or a conversion or 1 or multiple substituted and and aryl is unsubstituted or 1 or multiple substituted ₁ -C ₈ - alkyl -Aryl; or alkyl is saturated or unsaturated and linear or branched and unsubstituted or 1 or multiply substituted and heteroaryl is unsubstituted or 1 or By multiply substituted C ₁ -C ₈ -alkyl-heteroaryl is meant. ] The method of using the compound represented by these, the compound in the state of its base, or its pharmaceutically acceptable salt, for manufacturing the agent for treating migraine. 15. A compound of the general formula (I) is t-butyl- (7-methyl-2-
Pyridin-3-yl-imidazo [1,2-a] pyridin-3-yl) -amine,
t-Butyl- [2- (2,3-dimethoxy-phenyl) -5,7-dimethyl-imidazo [1,2-a] pyridin-3-yl) -amine, t-butyl- (2,5,7 -Trimethyl-imidazo [1,2-a] pyridine-3
-Yl) -amine, 3- (3-t-butylamino-5,7-dimethyl-imidazo [1,2-a] pyridin-2-yl) -phenol, t-butyl- (2-cyclohexyl-5,5. 7-Dimethyl-imidazo [1,2-a
] Pyridin-3-yl) -amine, 3- (3-t-butylamino-7-methyl-imidazo [1,2-a] pyridin-
2-yl) -phenol, t-butyl- (2-furan-2-yl-5,7-dimethyl-imidazo [1,2-
a] Pyridin-3-yl) -amine, t-butyl- (7-methyl-2-naphthalen-1-yl-imidazo [1,2-a]
] Pyridin-3-yl) -amine, t-butyl- [5,7-dimethyl-2- (5-nitro-furan-2-yl) -imidazo [1,2-a] pyridin-3-yl)- Amine, [5- (3-t-butylamino-7-methyl-imidazo [1,2-a] pyridin-2-yl) furan-2-yl] -methanol, t-butyl- [2- (5- [1,3] Dioxolan-2-yl-furan-2-yl) -7-methyl-imidazo [1,2-a] pyridin-3-yl] -amine, 5- (3-t-butylamino-5) , 7-Dimethyl-imidazo [1,2-a] pyridin-2-yl) -furan-2-carboxylic acid, t-butyl- (2-furan-2-yl-7-methyl-imidazo [1,2- a] Pyridin-3-yl) -amine, t-butyl- (7-methyl-2-pyridyl 2-yl - imidazo [1,2-a]
Pyridin-3-yl) -amine, t-butyl- (2-cyclohexyl-7-methyl-imidazo [1,2-a] pyridin-3-yl) -amine, t-butyl- (2,7-dimethyl- Imidazo [1,2-a] pyridin-3-yl) -amine, 5- (3-t-butylamino-7-methyl-imidazo [1,2-a] pyridin-
2-yl) -thiophene-2-carboxylic acid, t-butyl- (7-methyl-2-phenyl-imidazo [1,2-a] pyridine-
15. The method of claim 14 selected from the group consisting of 3-yl) -amine. 16. A compound represented by the general formula (I): Wherein R ¹ means H or C ₁ -C ₄ -alkanyl, where alkanyl is straight-chain or branched and unsubstituted or 1 or multiply substituted, And R ² is linear or branched and saturated or unsaturated and unsubstituted or mono- or multiply substituted C ₁ -C ₈ -alkyl radicals; saturated or unsaturated There and C ₃ -C ₈ are as or 1 or multiplexed substituted unsubstituted - cycloalkyl group; a saturated or unsaturated and unsubstituted or one or heterocyclyl group which is multiplexed substituted; Unsubstituted or mono- or multiply-substituted aryl group; unsubstituted or mono- or multiply-substituted heteroaryl group; alkyl saturated or unsaturated and Chain or branched and has and unsubstituted or 1 or and are multiplexed substituted cycloalkyl is saturated or unsaturated and unsubstituted or 1 or C ₁ -C being multiplexed substituted ₈ - alkyl -C ₃ -C ₈ - cycloalkyl; alkyl saturated or unsaturated and is or 1 or multiple substitutions is provided and unsubstituted branched or straight-chain and OriKatsu heterocyclyl C ₁ -C ₈ -alkyl-heterocyclyl which is saturated or unsaturated and is unsubstituted or mono- or multiply-substituted; alkyl is saturated or unsaturated and is linear or branched. C cage and the non location or a conversion or 1 or multiple substituted and and aryl is unsubstituted or 1 or multiple substituted ₁ -C ₈ - alkyl -Aryl; or alkyl is saturated or unsaturated and linear or branched and unsubstituted or 1 or multiply substituted and heteroaryl is unsubstituted or 1 or By multiply substituted C ₁ -C ₈ -alkyl-heteroaryl is meant. ], A compound represented by the formula (1) or a compound in the form of its base or a pharmaceutically acceptable salt thereof, A method used for the manufacture of a medicament for the treatment of blood, diabetes, meningeal salts, arteriosclerosis and / or for wound healing. 17. A compound represented by the general formula (I): Wherein R ¹ means H or C ₁ -C ₄ -alkanyl, where alkanyl is straight-chain or branched and unsubstituted or 1 or multiply substituted, And R ² is linear or branched and saturated or unsaturated and unsubstituted or mono- or multiply substituted C ₁ -C ₈ -alkyl radicals; saturated or unsaturated There and C ₃ -C ₈ are as or 1 or multiplexed substituted unsubstituted - cycloalkyl group; a saturated or unsaturated and unsubstituted or one or heterocyclyl group which is multiplexed substituted; Unsubstituted or mono- or multiply-substituted aryl group; unsubstituted or mono- or multiply-substituted heteroaryl group; alkyl saturated or unsaturated and Chain or branched and has and unsubstituted or 1 or and are multiplexed substituted cycloalkyl is saturated or unsaturated and unsubstituted or 1 or C ₁ -C being multiplexed substituted ₈ - alkyl -C ₃ -C ₈ - cycloalkyl; alkyl saturated or unsaturated and is or 1 or multiple substitutions is provided and unsubstituted branched or straight-chain and OriKatsu heterocyclyl C ₁ -C ₈ -alkyl-heterocyclyl which is saturated or unsaturated and is unsubstituted or mono- or multiply-substituted; alkyl is saturated or unsaturated and is linear or branched. C cage and the non location or a conversion or 1 or multiple substituted and and aryl is unsubstituted or 1 or multiple substituted ₁ -C ₈ - alkyl -Aryl; or alkyl is saturated or unsaturated and linear or branched and unsubstituted or 1 or multiply substituted and heteroaryl is unsubstituted or 1 or By multiply substituted C ₁ -C ₈ -alkyl-heteroaryl is meant. ] The pharmaceutical composition containing the compound represented by these, the compound in the state of its base, or its pharmaceutically acceptable salt, and a medicinal auxiliary agent. 18. A compound represented by the general formula (I): Wherein R ¹ means H or C ₁ -C ₄ -alkanyl, where alkanyl is straight-chain or branched and unsubstituted or 1 or multiply substituted, And R ² is linear or branched and saturated or unsaturated and unsubstituted or mono- or multiply substituted C ₁ -C ₈ -alkyl radicals; saturated or unsaturated There and C ₃ -C ₈ are as or 1 or multiplexed substituted unsubstituted - cycloalkyl group; a saturated or unsaturated and unsubstituted or one or heterocyclyl group which is multiplexed substituted; Unsubstituted or mono- or multiply-substituted aryl group; unsubstituted or mono- or multiply-substituted heteroaryl group; alkyl saturated or unsaturated and Chain or branched and has and unsubstituted or 1 or and are multiplexed substituted cycloalkyl is saturated or unsaturated and unsubstituted or 1 or C ₁ -C being multiplexed substituted ₈ - alkyl -C ₃ -C ₈ - cycloalkyl; alkyl saturated or unsaturated and is or 1 or multiple substitutions is provided and unsubstituted branched or straight-chain and OriKatsu heterocyclyl C ₁ -C ₈ -alkyl-heterocyclyl which is saturated or unsaturated and is unsubstituted or mono- or multiply-substituted; alkyl is saturated or unsaturated and is linear or branched. C cage and the non location or a conversion or 1 or multiple substituted and and aryl is unsubstituted or 1 or multiple substituted ₁ -C ₈ - alkyl -Aryl; or alkyl is saturated or unsaturated and linear or branched and unsubstituted or 1 or multiply substituted and heteroaryl is unsubstituted or 1 or By multiply substituted C ₁ -C ₈ -alkyl-heteroaryl is meant. ] Or a pharmaceutically acceptable salt thereof, which inhibits NO-synthase and / or septic shock, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, inflammation, inflammatory pain, cerebral pain A method of treating ischemia, diabetes, meningeal salts, arteriosclerosis and / or healing a wound. 19. In mammals, especially humans, which inhibits NO-synthase and / or septic shock, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, inflammation, inflammatory distress, cerebral ischemia, diabetes, marrow. In methods of treating membrane salts, arteriosclerosis and / or wound healing, general (I) Wherein R ¹ means H or C ₁ -C ₄ -alkanyl, where alkanyl is straight-chain or branched and unsubstituted or 1 or multiply substituted, And R ² is linear or branched and saturated or unsaturated and unsubstituted or mono- or multiply substituted C ₁ -C ₈ -alkyl radicals; saturated or unsaturated There and C ₃ -C ₈ are as or 1 or multiplexed substituted unsubstituted - cycloalkyl group; a saturated or unsaturated and unsubstituted or one or heterocyclyl group which is multiplexed substituted; Unsubstituted or mono- or multiply-substituted aryl group; unsubstituted or mono- or multiply-substituted heteroaryl group; alkyl saturated or unsaturated and Chain or branched and has and unsubstituted or 1 or and are multiplexed substituted cycloalkyl is saturated or unsaturated and unsubstituted or 1 or C ₁ -C being multiplexed substituted ₈ - alkyl -C ₃ -C ₈ - cycloalkyl; alkyl saturated or unsaturated and is or 1 or multiple substitutions is provided and unsubstituted branched or straight-chain and OriKatsu heterocyclyl C ₁ -C ₈ -alkyl-heterocyclyl which is saturated or unsaturated and is unsubstituted or mono- or multiply-substituted; alkyl is saturated or unsaturated and is linear or branched. C cage and the non location or a conversion or 1 or multiple substituted and and aryl is unsubstituted or 1 or multiple substituted ₁ -C ₈ - alkyl -Aryl; or alkyl is saturated or unsaturated and linear or branched and unsubstituted or 1 or multiply substituted and heteroaryl is unsubstituted or 1 or By multiply substituted C ₁ -C ₈ -alkyl-heteroaryl is meant. ] The method described above, which comprises administering an effective amount of the compound represented by the formula or a pharmaceutically acceptable salt thereof to the mammal.